Evaluating Cardiovascular Benefits of Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs) in Type 2 Diabetes Mellitus: A Systematic Review

Cardiovascular risks and complications remain elevated in patients with type 2 diabetes even after appropriate control of contributing factors like glycemic control, hypertension, and lipid profile. More efficient methods are needed to address this issue in type 2 diabetics. Newer drugs like glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown a cardioprotective effect in addition to glycemic control. This systematic review aims to study the latest literature findings on the cardiovascular effects of GLP-1 RAs in patients with type 2 diabetes. We used PubMed, Google Scholar, Science Direct, and Biomed Central databases for our data collection. Our review adheres to the 2020 Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. The outcomes evaluated in the review include major adverse cardiovascular events (MACE), heart failure, stroke, all-cause mortality, and effects on cardiovascular risk factors. After careful inspection and quality check, we included 14 articles in the systematic review. GLP-1 RAs were associated with a significant reduction in cardiovascular mortality, all-cause mortality, nonfatal myocardial infarction (MI), and nonfatal stroke, especially in patients with existing cardiovascular risk factors. However, more evidence is required to determine if these benefits extend to those without such risk factors. Limited data suggest that GLP-1 RAs might have a protective effect on arrhythmias, but this area needs further investigation. Despite their potential, several barriers hinder the widespread use of GLP-1 RAs. In conclusion, GLP-1 RAs significantly reduce cardiovascular mortality, all-cause mortality, nonfatal MI, and stroke, with minor effects on hospitalization due to heart failure. Benefits are greater in patients with cardiovascular risk factors. A comprehensive, multilevel approach to policy development and implementation is necessary to optimize the use of these medications in eligible populations.


Introduction And Background
One of the most significant public health concerns of the twenty-first century is type 2 diabetes.By 2025, according to rising prevalence rates, approximately 570 million cases of the illness worldwide are projected, which will pose an economic and social burden globally [1,2].Individuals with type 2 diabetes face a heightened risk of developing cardiovascular conditions, such as myocardial infarction (MI), heart failure (HF), stroke, peripheral artery disease, and cardiovascular death.Aggressive glucose-lowering treatments have not been convincingly effective in lowering cardiovascular morbidity and mortality in diabetes patients at high cardiovascular risk.Addressing cardiovascular complications of type 2 diabetes remains an unmet need, with its associated expenditures related to medications, hospitalizations, and interventions posing a significant financial burden [3].Substantial evidence suggests that the novel glucose-lowering agents, particularly glucagon-like peptide-1 receptor agonists (GLP-1 RAs), reduce the incidence of significant cardiovascular events in those who have type 2 diabetes [4][5][6].

GLP-1 RAs
Glucagon-like peptide-1 (GLP-1) is a short peptide hormone produced by gastrointestinal L cells in response to nutrition consumption.Various human tissues, including pancreatic islets, stomach, brain, endothelial cells, lungs, kidneys, smooth muscle cells, and particular atrial and ventricular cardiomyocytes, exhibit GLP-1 expression.GLP-1 binds to the GLP-1 receptor and causes incretin actions such as glucose-dependent insulin production from pancreatic β cells, suppression of glucagon release from pancreatic α cells, and delayed gastric emptying.Together, these effects reduce blood glucose levels and promote postprandial glucose metabolism.Additionally, GLP-1 stimulates glucagon-like peptide-1 receptor (GLP-1R)-expressing hypothalamus neurons, which promote satiety and weight reduction.GLP-1 has a half-life of only a few minutes due to its cleavage by the ubiquitously expressed enzyme dipeptidyl peptidase-4 (DPP4).GLP-1 RAs are peptides identical to human GLP-1, cannot be cleaved by DPP4, and are complete agonists of GLP-1R.

Cardiovascular effects of GLP-1 RAs
Data from large-scale cardiovascular outcome trials (CVOTs) have shown a significant and persistent decrease in atherothrombotic events, particularly among patients with preexisting atherosclerotic cardiovascular disease [7][8][9][10][11][12].All available GLP-1 RAs have an impact on cardiovascular risk factors.GLP-1 RA reduces systolic blood pressure by 2-6 mmHg, linked to reduced cardiovascular events.Previous findings from hypertension studies indicate that lowering blood pressure leads to a considerable reduction in major adverse cardiovascular events (MACE).Regarding lipids, GLP-1 RA lowers total cholesterol, low-density lipoprotein (LDL), and triglycerides, indicating a possible positive impact.Various experimental data have shown that GLP-1 and GLP-1 RA reduce the development and progression of atherosclerotic lesions by resulting in more stabilized and less vulnerable plaques, most likely due to antiatherogenic and antiinflammatory effects in endothelial cells, monocytes, macrophages, and vascular smooth muscle cells that express GLP-1R [4][5][6].
The placebo-controlled cardiovascular outcome trials examined MACE, nonfatal MI, stroke, or all-cause mortality.A decreased incidence of MACE was observed in four of the studies, namely LEADER for liraglutide (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results), SUSTAIN 6 for weekly semaglutide (Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects With Type 2 Diabetes), Harmony Outcomes for albiglutide, and REWIND for dulaglutide (Researching Cardiovascular Events With a Weekly Incretin in Diabetes).These findings have led to the prioritizing of novel anti-hyperglycemic drugs for secondary prevention of unfavorable cardiovascular consequences in individuals with type 2 diabetes [8][9][10][11][12].
Despite the robust evidence supporting their use, integrating GLP-1 RAs into routine clinical practice remains suboptimal.Barriers such as cost, patient adherence, and physician familiarity with these therapies persist [13].Overcoming these challenges through policy and education is crucial to enhancing the utilization of GLP-1 RAs, ultimately improving cardiovascular outcomes in the diabetic population.
In this systematic review, we have included clinical trials, meta-analyses, and systematic reviews published from 2020 to 2024.We aim to gather the latest findings from the literature on cardiovascular risks and benefits assessment in type 2 diabetes patients on GLP-1 RAs.We also aim to analyze the underuse of GLP-1 RAs in clinical practice despite the increasing evidence demonstrating their efficacy.Outcomes evaluated in the review include MACE, heart failure, stroke, all-cause mortality, and effects on cardiovascular risk factors.

Review Methods
Our review adheres to the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [14].

Database and Search Methodology
We performed our data search from April 22, 2024, to April 30, 2024.We used PubMed, Google Scholar, Science Direct, and Biomed Central databases for our data collection.Additionally, grey literature, including unpublished studies, reports, and theses, was used as a source.We searched for studies related to cardiovascular outcomes in type 2 diabetic patients on GLP-1 or dual GLP-1/gastric inhibitory polypeptide (GIP).

Inclusion and Exclusion Criteria
We included clinical trials, systematic reviews, and meta-analyses published in English between 2020 and 2024.The studies had to involve adults aged 18 and above diagnosed with type 2 diabetes mellitus and examine the cardiovascular effects of GLP-1 RAs or dual GLP-1/GIP therapies.We focused on studies reporting MACE, heart failure, stroke, all-cause mortality, and cardiovascular risk factors.We considered only articles available as free full-text.We excluded animal studies, in vitro studies, case reports, editorials, commentaries, studies involving type 1 diabetes patients, children, or patients with renal failure, and articles published before 2020 or in languages other than English.

Data Extraction
We aimed to include only high-quality studies in this systematic review.Two authors independently screened and extracted data based on the established inclusion and exclusion criteria.We resolved differences in opinions through consensus, seeking a third reviewer's opinion as needed.

Search Results
The literature search conducted through PubMed, Google Scholar, Science Direct, Biomed Central, and grey literature sources via MedRxiv yielded 3,335 articles.After applying filters and removing duplicates, we screened the remaining articles by title and abstract.Two independent reviewers conducted this screening, resulting in the exclusion of 733 irrelevant articles.In addition, we excluded 58 articles due to the unavailability of free full text.After thoroughly reviewing the full-text versions, we excluded 39 more articles.Ultimately, we assessed the quality of 18 articles and included 14 high-quality studies in our review.
Refer to Figure 1 for the detailed PRISMA flow chart [14].

Critical Appraisal
For quality appraisal, we used the Cochrane risk of bias assessment for randomized controlled trials (RoB 2), the Newcastle-Ottawa Scale (NOS) for observational trials, and the Assessment of Multiple Systematic Reviews (AMSTAR 2) checklist for systematic reviews and meta-analysis.We included only studies fulfilling the criteria of quality defined by AMSTAR 2, NOS, and RoB2 in the review [15][16][17].Tables 2-5 show the detailed quality assessment of the included studies.

MACE
GLP-1 RAs and their various beneficial effects have been a topic of interest ever since their introduction in 2005, and various studies have been conducted on them [7][8][9][10][11][12].While the standard MACE definition includes cardiovascular death, nonfatal MI, and nonfatal stroke, some studies expand this definition to include other relevant cardiovascular outcomes.This broader definition helps capture the full cardiovascular benefits associated with GLP-1 RAs.A systematic review and meta-analysis of the eight significant CVOTs between GLP-1 RA and insulin was done by Evans et al. in 2023.Their studies showed that GLP-1 RA showed a significantly better cardiovascular outcome when compared to basal insulin (hazard ratio (HR): 0.62; 95% confidence interval (CI): 0.48-0.79;I 2 = 82%) [25].The pre-existing cardiovascular risk factors of the populations included in their studies may have influenced the extent of these benefits.
Giugliano et al. also reinforced the cardioprotective effects of GLP-1 RAs in their meta-analysis of the eight CVOTs in 60,080 patients in 2021.They found that the risk of MACE was reduced by 14% compared to placebo and that this effect was more pronounced in people with pre-existing cardiovascular risk factors than in people without (16% and 6%, respectively) [24].Huang et al. confirmed the clinical outcomes of GLP-1 RAs observed in the LEADER trial through their retrospective cohort study [29].They proved that the reduction in MACE and cardiovascular risk factors observed in clinical trials applied to a broader population group in the real world.
Studies also compared the anti-atherosclerotic effect of GLP-1 RA with other novel anti-hyperglycemic agents.Longato et al., in their retrospective study comparing patients on GLP-1 RA and DDP4 inhibitor (DPP4i), found that the former had a better cardiovascular outcome when compared to the latter, irrespective of the sex and pre-existing cardiovascular risk factors [28].Their study favored the hypothesis that the anti-atherosclerotic protective effect could also apply to patient populations without pre-existing atherosclerotic cardiovascular diseases.Piccini et al. further outlined this finding in their retrospective cohort study.They observed that GLP-1 RAs enabled a long-lasting decrease in HbA1c over time.This improvement in glycemic control with a longer duration of treatment with glucagon-like peptides (GLPs) could be a potential mediator of cardiovascular benefits, responsible for up to 82% of the total reduction in atherosclerotic events, even in those without a history of cardiovascular diseases [27].

Heart Failure
Giugliano et al. also found that GLP-1 RAs decreased the risk of hospitalization due to heart failure by 10% (HR: 0.90; 95% CI: 0.83-0.98;P = 0.023) [24].Their observation was limited because none of the studies included in their analysis considered heart failure a primary outcome.Also, this observation could have , who found that the risk was increased in patients on insulin, though there was no significant difference among the various second-line agents used [23,[25][26].Further comprehensive studies are necessary to establish definitive conclusions regarding the benefits of GLP-1 RAs on heart failure.

Stroke
GLP-1 RAs have demonstrated a significant capacity to reduce stroke events compared to other treatment modalities.Kunutsor et al. found a substantial reduction in the risk of overall stroke (HR: 0.85; 95% CI: 0.77-0.93),fatal stroke (HR 0.72; 95% CI: 0.52-1.00),and nonfatal stroke (HR: 0.81; 95% CI: 0.71-0.93).These findings indicate that factors beyond glycemic control, such as improvements in blood pressure, lipid levels, and weight management, may contribute to the benefits of GLP-1 RAs in reducing stroke.Additionally, the anti-inflammatory properties of GLP-1 RAs and their ability to reduce oxidative stress may be crucial in lowering the risk of stroke [23].Supporting these findings, Evans et al. showed that GLP-1 RAs reduced the incidence of stroke more significantly than insulin, with a hazard ratio (HR) (95% CI) of 0.50 (0.40-0.63).The study highlighted a 16% reduction in the risk of nonfatal stroke, emphasizing the superior efficacy of GLP-1 RAs in stroke prevention compared to traditional insulin therapy [25].
Furthermore, Huang et al. discovered that patients treated with liraglutide, a specific GLP-1 RA, had a significantly lower risk of stroke (HR: 0.54; 95% CI: 0.34-0.87).This study also highlighted the broader cardiovascular benefits of liraglutide, including a reduced risk of a composite cardiovascular outcome, lower all-cause mortality, and reduced healthcare costs related to cardiovascular events [29].These studies suggest that GLP-1 RAs provide substantial cardiovascular benefits beyond glycemic control.These benefits include improvements in blood pressure, lipid profiles, weight management, anti-inflammatory effects, and reduction of oxidative stress.These multifactorial advantages position GLP-1 RAs as a superior treatment option for reducing stroke and other cardiovascular events in type 2 diabetes patients.Additionally, GLP-1 RAs significantly reduced the risk of hospitalization for heart failure by 10% (HR: 0.90; 95% CI: 0.82-0.99;P = 0.023) and provided robust benefits in reducing the incidence of macroalbuminuria by 26% (HR: 0.74; 95% CI: 0.67-0.82;P < 0.001) [24].These findings emphasize the potential of GLP-1 RAs as a preferred treatment option for type 2 diabetic patients who are at high risk of cardiovascular events.

Cardiovascular Risk Factors
Qin et al. undertook a meta-analysis on the major CVOTs, including the EXSCEL trial, LEADER study (liraglutide), SUSTAIN 6 study (semaglutide), Harmony Outcomes study (albiglutide), ELIXA study (Evaluation of Lixisenatide in Acute Coronary Syndrome), and REWIND study (dulaglutide).They observed that no studies investigated the differences between the various classes of GLPs and their cardio-protective profiles and that their effects might differ based on their structure or potency.Improvements in cardiovascular risk variables such as HbA1c, systolic blood pressure, body weight, and anti-inflammatory pathways may explain the cardioprotective effects of GLPs.Specifically, GLP-1 RAs reduced the risk of death from cardiovascular causes by 10% (RR: 0.90; 95% CI: 0.83-0.97;P = 0.004) and reduced the risk of stroke (fatal or nonfatal) by 15% (RR: 0.85; 95% CI: 0.77-0.94;P = 0.001).GLP-1 receptors in cardiac and vascular tissues also improve endothelial function, cardiac output, and myocardial glucose uptake [20].Tuttolomondo et al. also reinforced these findings.They observed that patients treated with dulaglutide showed significantly better metabolic profiles, with a 26% reduction in macroalbuminuria (HR: 0.74; 95% CI: 0.67-0.82;P < 0.001), which was associated with positive findings on vascular health markers like arterial stiffness and endothelial function markers [30].Zhang et al. also confirmed these findings by demonstrating that treatment with GLPs reduced the carotid intima-media thickness (CIMT) significantly by -0.14 mm (95% CI: -0.25, -0.02; P = 0.016) compared to insulin therapy, which correlated to reduced low-density lipoprotein and eventually delayed the development of atherosclerotic cardiovascular disease [31].

Challenges in Prescription
Scheen et al. observed that the clinical use of GLPs remains low even though there is increasing evidence regarding the efficacy of these novel agents in reducing cardiovascular complications.Prescriptions for medications like sulfonylurea, DPP4is, and insulin continue to increase [18].Reluctance from the side of prescribers and patients, gastrointestinal adverse effects, the high price of the medication, and difficulties in navigating the healthcare system are some of the reasons for this trend.Huang et al. in their study observed that the liraglutide group had reduced median per-patient per-month (PPPM) inpatient as well as emergency room, and total medical expenditures when compared to the baseline insulin group but higher median PPPM outpatient, total pharmacy, and total costs (all P < 0.0001).This observation led to the inference that patients on GLPs had higher pharmacy costs but lower medical costs when compared to insulin users, which, in effect, decreased overall medical expenditure [29].Available data from studies have demonstrated that improved clinical outcomes balance the higher cost.Efforts should be made at multiple levels, from clinicians to pharmaceutical companies to payers to patients, to ensure the affordability of the medication.

Strengths and limitations
This systematic review included real-world, good-quality studies and multinational trials with large sample sizes and long follow-up periods, which helps minimize the risk of unreliable results.Our review comprised only observational studies, systematic reviews, and meta-analyses characterized by a low risk of bias.The benefits of GLP-1 RAs in reducing arrhythmia and atrial fibrillation were not evaluated in any of the included studies.Also, no studies have compared the efficacy of the different classes of GLPs and their cardioprotective profiles.Excluding studies published before 2020, studies published in languages other than English, and articles unavailable as full-text could be a few of the other limitations of the review.

Conclusions
GLP-1 RAs are associated with a significant reduction in cardiovascular mortality, all-cause mortality, nonfatal MI, and nonfatal stroke.Although studies have demonstrated a decreased risk of hospitalization from heart failure, this was a minor protective effect and warranted more studies for definitive evidence.The benefits of GLP-1 RAs were more pronounced in inpatient populations with existing cardiovascular risk factors, and more evidence is needed to ascertain whether these results apply to those without any cardiovascular risk factors.Also, more studies are needed to compare the efficacy of the different classes of GLPs and their cardioprotective profiles.A multilevel approach to devise and execute policies is needed to overcome prescription barriers and to ensure optimal usage of these drugs in eligible populations.

FIGURE 1 :
FIGURE 1: PRISMA flow diagram PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analysis been due to the overall atherosclerotic risk reduction benefits of the class of drugs.Heart failure risk reduction was also observed in a few other studies including Evans et al. (HR: 0.57; 95% CI: 0.35-0.92),Kunutsor et al. (pooled HR (95% CI) of 0.92 (0.84-1.00)) and Thein et al. in 2020

Table 1
lists the search strategy, keywords, and medical subject headings (MeSH) used for data collection.

Table 6
[20]s the study characteristics of the final 14 articles in the review.Author Type of studyQuality assessment tool Quality scoreScheen et al.[18]Systematic review and meta-analysis AMSTAR 2 High-quality review Rahman et al.[19]Systematic review and meta-analysis AMSTAR 2 High-quality review Qin et al.[20]

TABLE 2 : Critical appraisal of included studies
AMSTAR 2: Assessment of Multiple Systematic Reviews; RoB 2: Cochrane risk of bias assessment for randomized controlled trials

TABLE 3 : AMSTAR 2 checklist for systematic reviews and meta-analysis
AMSTAR 2: Assessment of Multiple Systematic Reviews; RCT: randomized controlled trials; NRSI: non-randomized studies of interventions

TABLE 5 : Cochrane risk of bias assessment for randomized controlled trials
This is a meta-analysis of trial data, which is inferior to patient-level meta-analysis.The study used aggregate data, so patient subgroups (with and without cardiovascular disease) could not be investigated.cardiovascular disease) Differences in gender were not considered, and the possible superiority of a drug within the GLP1-RA class was also not investigated.Differences in the patient population, research designs, comparators, follow-up periods, and end goals can cause heterogeneity in studies, which can limit the interpretation.The difference in body weight of the patients can contribute to the findings observed but was not accounted for in the study.The duration of